The research described in this proposal is designed to elucidate the functional role and basic mechanisms of action of two substances that we propose function as key neuro transmitters/neuromodulators in the control of active sleep and wakefulness within the laterodorsal tegmental and the pedunculopontine nuclei (LDT/PPT) and the nucleus pontis oralis (NPO). These neuroactive substances are GABA, which is a major inhibitory neurotransmitter in the central nervous system, and hypocretin, which is a newly discovered neuropeptide that is manufactured by cells that reside exclusively within the hypothalamus. Based upon our Preliminary Studies, we hypothesize that a waking-on group of hypocretinergic cells in the hypothalamus project to the LDT/PPT to induce wakefulness, and that there is another distinct group of hypocretinergic cells that discharge only during active sleep which, we believe, project to the NPO to promote active sleep. In addition, we hypothesize that within the LDT/PPT there are GABAergic cells that inhibit waking-on neurons and that other local circuit GABAergic neurons in the NPO inhibit active sleep-on neurons. Guided by these hypotheses, we intend to examine the precise cellular mechanisms of action of GABA and hypocretin within the LDT/PPT and NPO in the initiation and maintenance of active sleep and wakefulness. In addition to providing key data that will describe the basic cellular mechanisms of action of GABA and hypocretin within the LDT/PPT and NPO, vis-a-vis active sleep and wakefulness, we believe that the veracity of a number of basic principles of state-dependent control will be verified, First, we propose that primary consideration should be given to the site of action of putative neurotransmitters/neuromodulators in research and clinical studies of sleep and wakefulness, i.e., site- specificity of effect. Second, that inhibitory substances should not necessarily be assumed to suppress physiological processes, but that they an result in "aroused" types of behaviors, and that excitatory substances can, in a similarly paradoxical fashion, initiate "quiescent" behaviors, such as sleep. Finally, we suggest that both excitatory and inhibitory drives, and their state-dependent interactions, must be taken into account when examining the excitability of neurons in conjunction with the control of behavioral states. Resolution of our hypothesis and of the principles upon which they are based will provide important foundational bases for understanding the neuronal mechanisms that control active sleep and wakefulness. In addition, the data that we will obtain will be directly applicable to the development of rational therapies for the treatment of sleep disorders that arise as a result of the pathological functioning of these mechanisms.